Substituted thiobarbitubic acids



Patented Jan. 30, 1945 SUBSTITUTED THIOBARBITURIC ACIDS AND SALTS THEREOF Lewis A. .Walter and Louis B. Goodson, East Orange, N. J., assignors to The Maltbie Chemical Company, Newark, N. 3., a corporation of- New Jersey NoDrawing. Application April 23, 1943,

Serial No.484 ,316 a 17 Claims.

The present invention relates to certain new and useful chemical compounds, viz. 5,5 disubstituted thiobarbituric acid derivatives, and their salts, having the formula:

wherein R and R are hydrocarbon groups,

either saturated or unsaturated, and either the 1 (sit) i g and R has a carbon atom attached directly to the carbon atom forming the barbituric acid nucleus; and wherein X is a member of a group consistingof hydrogen, alkali-metal, an equivawherein a and-R have the significance stated lent of alkaline earth metal, ammonium, monoalkyl ammonium, dialkyl ammonium, alkanol ammonium and an equivalent of alkylene diammonium.

These novel thiobarbituric acid compounds and their salts, when tested pharmacologically, have been found to possess useful and valuable hypnotic and sedative properties, making them valuable for various medical purposes. The compounds are, in general, pale yellow in color, and are generally crystalline solids.

In general, the following method has been found desirable, and is the best now known to us, for the preparation of our novel thiobarbituric acid derivatives herein described; but other methods of synthesis may also be employed, as

for example, synthesis through the corresponding disubstituted cyano acetic ester.

5- etn ltzzieemvz-s-aeemyz thiobarbituric acid According to what is at present a preferred.

procedure for synthesis, a disubstituted malonic ester is condensed with thiourea in thepresence of sodium ethoxide in absolute ethanol, as is illustrated by the following equation:

above and R" is a lower alkyl group. When the reaction is complete, the solvent is removed by distillation and the residue dissolved in water- The resulting solution is then extracted with ether and the aqueous layer separated and acidi- 1 fied. A precipitate of crude thiobarbituric acid results, which may be purified by crystallization from a suitable solvent such ,as ethanol. In those cases in which the material does not crystallize readily, it is washed with sodium bicarbonate solution, dried, and converted to the sodium' salt with sodium ethoxide in absolute ethanol; on cooling, the sodium salt crystallizes as an alcoholatewhich is purified by crystallizing from absolute alcohol.

The disubstituted malonic esters may be prepared readily by condensing beta chloroethyl sulfides with sodio 'monoalkyl malonic esters,

preferably in an inert solvent such as toluene or benzene, as illustrated by the following equation:

' 000R", ascmomcl Na h-n ooR ascmcg, coon'" c NaCl R, coon" Salts of the compounds may be prepared as hereafter described.

The following specific examples are illustra I tive of the novel compounds according to our invention:

EXAMPLE 1 To '1.1 moles of sodium dissolved in 500 cc. of absolute alcohol, and 0.5 mole of B-ethylthioethyl isoamyl malonic ester (boiling point lilo-133 C.-

at 1 mm.), 0.6 mole of thiourea is added. This. mixture is refluxed on a steam bath for 12 hours, the alcohol is removed by vacuum distillation and the residue is dissolved in about 600 cc. of

water. The resulting solution is extracted with j V ether and the aqueous layer is separated andacidified, yielding a precipitate of 5-p-iethylthioethyl fi-isoamyl thiobarbituric acid. This crude product is filtered off and purified by crystallization from alcohol. It has a melting point o i v 3 approximately ill-113 C. (uncorrected), and is r presented by the formula:

I 2368,33 3 UNITED STATES PATENT O FICE Y Exmru 2 S-p-n-butylthioethul-S-isoflml thiobarbituric acid This compound is prepared by condensing 0.5

mole oi fl-n-butylthioethyl isopropyl malonic' ester (boiling point 130-133" C. at 1.5 mm.), 0.6

mole of 'thiourea, and 1.1 moles of sodium ethoxide in 500 cc. absolute alcohol in the'sanie manner described in Example 1. The crude product does not crystallize readily so it .is dissolved in ether, filtered free of colloidal material and diluted with'ligroin. The product was found to crystallize, and to.have a melting point of approximately 68-l0 C. It is represented by the formula: a

cmcmomcmscmom CO-NH OH: H C

COl IH at Exempt! 3 s-p-n-buwztmoethuas-azz z thioburbituric acid -This compound is prepared from 0.5.mole of I fl-n-butylthioethyl allyl malonlc ester (boiling lute alcohol; n cooling the sodium alt crystalllzes as an alcoholate, and it is recrystallized from absolute alcohol. This sodium salt is dried in a vacuum over sulfuric acid toremov alcohol. The free barbiturlc acid obtained by acidification of an aqueous solution of the sodium salt is a waxlike compound. It is represented by the formula).

cmcmcmoms-cmcn CO-NH n c s at capo-cm co-Nn the'foregoing examples, it will be observed that the substituent groups R and R, as

defined above, are capableloi considerable variation within those limits while producing useful and valuable compounds. Among the derivatives.

specifically included in the invcntig are the followingflllustrativeexamples of our novel derivatives, including the .speciflccompounds previously described, and which, when [tested pharmacologically, were round to possess valuable and useful properties as hypnotics or sedatives Thiobai'biturlcpclil ascmcm c o-Nn Approximate I itt R CO-NH wherein: m

I auaa- I C. Eth Ally 101-103 50.1. Isoamyl- 111- Ally! n-Buty 100.54 0 n-Blltyl Ethyl 64-66 Dom. Isopropyl 68-7!) L tilt 3'1? n nm y i-mctiiylbuty o Oil.

Novn. THIOBARBI'IURIC Acm Dmuvamrs Sodium salts or the thiobarbiturlc acids described above may be prepared by dissolving one equivalent oi the disubstituted barbituric acid in a 15-20% solution of one equivalent oi. sodium ethoxlde in absolute alcohol. 0n cooling, the sodium salt usually crystallize as an alcoholate which may be dried in a vacuum to remove the Sears or m alcohol. Many Ofthe sodium salts so obtained are hygroscopic powders and are readily soluble in water; these aqueous solutions are alkaline in reaction. When administered orally, or hypodermically, in proper dosage they are good and useful hypnotics or sedatives. I I

Calcium salts may be prepared by treating an absolute alcohol solution of the sodium salt witlr the metathetical amount 01' alcoholic calcium chloride, filtering oil the precipitated sodium chloride and concentrating the alcoholic solution to yield the calcium salt.

The ammonium, alkyl and alkanol ammonium salts may be prepared by dissolving the corresponding thiobarbituric acid in an excess of ammonia or amine and subsequently removing the excess quantity or base;

In the following claims it is to be understood that thiobarbituric acid derivative and similar expressions, includes, also, the salts of such derivatives, such as, {or example, the salts described above.

The examples given above, and illustrative processes for their production, include the best embodiments oi our present invention now known to us; but it is to be understood that the inventionis not necessarily or specifically limited thereto and may, under proper conditions, have n n o was i.

1H, H C =8 a o-ilrx and R has a ,carbon atom attached directly to the carbon atomforming the thiobarbituric acid nucleus; and wherein X is a member of a group consisting of hydrogen, alkali-metal, an equivalent of alkaline earth metal. ammonium, mono- "alkyl ammonium, dialkyl ammonium, .alkanol ammonium, and an equivalent or alkylene (ii-- ammonium.

2. A compound according X represents hydrogen;

3. A compound according to claim 1 in which at least one or the-R and 3' groups is a primary hydrocarbon group.

to claim awmcu' hydrocarbon group and X represents hydrogen.

5. A compound according to claim 1 in which R and R are both primary hydrocarbon groups.

6. A compound according to claim 1 in which R and R are both primary hydrocarbon groups and X represents hydrogen.

7. A compound according to claim 1 in which R is a primary hydrocarbon group containing 4 carbon atoms and R is a primary hydrocarbon group. a

8. A compound according to claim 1 in which R is a primary hydrocarbon group containing 4 carbon atoms, R' is a primary hydrocarbon group and X represents hydrogen.

9. A compound according to claim 1 in which R is a n-butyl grou and R is a primary hydrocarbon group.

10. A compound according to claim 1 in which R is a n-butyl group, R is a primary hydro- 14. A compound. according to claim 1 in which R is a secondary hydrocarbon group, R is a primary hydrocarbon group and X represents hydrogen.

5 15. 5-5-n-butylthioethyl-5-allyl thiobarbituric acid, having the formula:

1s. 5- 3-(1-methyl butyl) -thioethyl 5 ethyl thiobarbituric acid, having the formula: 15

1 7. fi-p-n-butylthioethyl-5-isopropy1 thiobarbituric acid, having the formula:

LO IS H. GOODSON. 

